Roles of IL-6, TNF-a and IL-1B in Regulating Growth Hormone Signaling and FGF19 Signaling in the Liver

Growth failure is a major complication of inflammatory diseases including inflammatory bowel disease. Evidence suggests that during inflammation, the liver becomes resistant to growth hormone (GH) actions, leading to downregulation of the anabolic gene IGF-I and the activation of catabolic processes. Decades of studies demonstrated that pro-inflammatory cytokines IL-6, TNF-alpha and IL-1beta are involved in the pathogenesis of hepatic GH resistance. However, the exact mechanisms used by these individual cytokines to regulate GH signaling are not defined. Using Huh-7 human hepatoma cells and mouse models of chronic and acute inflammation, we show that TNF-alpha and IL-1beta but not IL-6 inhibited hepatic GH receptor (GHR) expression, and that IL-6 but not TNF-alpha and IL-1beta stimulated expression of suppressor of cytokine signaling-3 (SOCS3). TNF-alpha/IL-1beta and IL-6 acted primarily at GHR and SOCS3 respectively to inhibit the GH-IGF-I pathway. While TNF-alpha/IL-1beta exerted a tonic inhibition on hepatic GH signaling, IL-6 activity is dependent on the active GH pathway. IL-6 lost its inhibition on the GH-IGF-I pathway when GHR expression was blocked as the inflammation progressed. These results reveal previously undefined distinct mechanisms used by TNF-alpha/IL-1beta and IL-6 to inhibit the hepatic GH pathway. Our results may provide a new guidance for clinical practice in treating pediatric inflammation-induced GH resistance.;Taken together, our results demonstrate that IL-6, TNF-alpha and IL-1beta play different roles in regulating the GH and FGF-19 pathways in the liver.beta;Fibroblast growth factors (FGFs) play critical roles in many physiological processes by binding to and activating FGF receptor (FGFR) family. FGF19 belongs to FGF15/19 subfamily of FGFs that includes FGF15/19, FGF21 and FGF23. FGF19 has been shown to regulate bile acid homeostasis, and protein and glycogen synthesis in the liver. FGF19 binds FGFR4 and the co-receptor beta-klotho to initiate signaling. Studies have shown that proinflammatory cytokines such as TNF-alpha can impair FGF21 signaling in adipose cells by repressing the expression of beta-klotho. However, little is known about the effects of IL-6, TNF-alpha and IL-1beta on regulating hepatic FGF19 signaling. In the present study, we found that IL-1beta inhibited beta-klotho expression both in vitro and in vivo, and this inhibition required JNK and NF-kappaB pathways. IL-6 and TNF-alpha did not inhibit beta-klotho expression in Huh-7 cells.